In contrast to the properties disclosed by the present invention, the prior art is based on is [1,4]diazepino[6,7,1-hi]indoles for which antagonist properties with respect to cholecystokinin (CCK) and/or gastrin are described, and which are proposed for complaints of the digestive tract: stomach, intestine, pancreas and gall bladder, and in particular eating disorders.
Thus, European patent application No. 340,064 describes compounds of formula: ##STR2## in which R.sub.1 and R.sub.2 are hydrogen or halogen, Ar is indolyl or phenyl and n is 2 or 3. These compounds are peripheral cholecystokinin antagonists (CCK.sub.A).
European patent application no. 360,079 describes peripheral and/or central CCK-antagonist compounds of formula: ##STR3## in which R.sup.1 is optionally substituted aryl, X is oxygen or methylene optionally substituted with a lower alkyl radical, A is a bond or lower alkylene which may have one or more lower alkyl groups, and R.sup.2 is hydrogen or acyl. Unpublished French patent application No. FR 94/12282 describes the application of diazepinoindole derivatives of formula ##STR4## in which R is hydrogen, lower alkyl or lower alkoxy, and A is an optionally substituted aromatic ring, some of which derivatives are novel, for the preparation of medicinal products intended for the treatment of complaints that fall within the scope of a phosphodiesterase 4 inhibitor.
As regards the inhibition of phosphodiesterases, it is recalled that adenosine 3', 5'-cyclic monophosphate (cAMP) is a ubiquitous intracellular second messenger, which is intermediate between a first messenger (hormone, neurotransmitter or autacoid) and the functional responses of the cell: the first messenger stimulates the enzyme responsible for the synthesis of cAMP; depending on the cells under consideration, the cAMP then becomes involved in a great many functions: metabolic, contractile or secretory.
The effects of cAMP come to an end when it is degraded by cyclic nucleotide phosphodiesterases, intracellular enzymes which catalyze its hydrolysis into inactive adenosine 5'-monophosphate.
In mammals, it is possible to distinguish at least five major classes of cyclic nucleotide phosphodiesterase (PDE) numbered from 1 to 5 according to their structure, their kinetic behavior, their substrate specificity or their sensitivity to effectors (Beavo J. A. et al. (1990) Trends Pharmacol. Sci. 11, 150-155. Beavo J. A. et al. (1994) Molecular Pharmacol. 46, 399-405). The PDEs 4 are specific for cAMP.
Nonspecific phosphodiesterase inhibitor compounds are known, these inhibiting several classes of enzymes. This is the case for certain methylxanthines such as theophylline. These compounds have a low therapeutic index, in particular on account of their action on types of PDE present in cells other than the target cells. In contrast, certain classes of PDE can be selectively inhibited by various pharmacological agents: hydrolysis of the cyclic nucleotides is slowed down and thus their concentration increases only in those cells containing the type of PDE which is sensitive to the inhibitor.
Particular interest is evident for phosphodiesterases 4 (PDEs 4), which have been identified in many tissues including the central nervous system, the heart, vascular endothelium, vascular smooth muscle and that of the airways and the myeloid and lymphoid lines.
An increase in cAMP in the cells involved in inflammation inhibits their activation: inhibition of the synthesis and of the release of mediators at the level of mastocytes, monocytes, eosinophil and basophil polymorphonuclear leukocytes, inhibition of chemotaxis and of the degranulation of neutrophil and eosinophil polymorphonuclear leukocytes and inhibition of lymphocyte division and differentiation.
Cytokines, in particular TNF and interleukins, produced by various types of leukocyte such as T lymphocytes and eosinophil polymorphonuclear leukocytes, play an important role in the triggering of inflammatory manifestations, in particular in response to stimulation by an allergen in the respiratory pathways.
Moreover, cAMP reduces the tonus of smooth muscle fibers in the airways; PDE 4 inhibitors bring about bronchial relaxation.
It is thus possible to expect that PDE 4-selective inhibitors will possess a therapeutic activity as antiinflammatory, antiallergic and bronchodilatory medicinal products, and in the treatment of asthma, in which infiltration of the airways by inflammatory cells and bronchoconstriction are observed.
Theophylline has been very widely used for a long time in the treatment of asthma, and, although its mechanism of action is complex, the inhibition of PDE contributes to its action, but also to certain undesirable effects such as nausea and headaches.
In recent years, extensive research has been carried out in order to obtain and develop powerful PDE 4 inhibitors. This proves to be difficult on account of the fact that many potential PDE 4 inhibitors are not devoid of activity on the phosphodiesterases of other classes.
At present, the lack of selectivity of PDE 4 inhibitors thus represents a considerable problem, given the extent of the functions regulated by cAMP, the said problem still needing to be considered as poorly resolved or unresolved. There is thus a need for powerful and selective PDE 4 inhibitors, that is to say inhibitors which have no action with respect to the PDEs belonging to other classes.
Thus, rolipram (INN), a pyrrolidone derivative first synthesized in 1975, is considered to be representative of PDE 4-specific inhibitors. Many compounds related to rolipram have been synthesized with a view to their use as PDE 4 inhibitors. In vitro, rolipram inhibits the activity of inflammatory cells in rodents: inhibition of the synthesis of mediators by mastocytes, eosinophil and basophil polymorphonuclear leukocytes and monocytes; inhibition of chemotaxis and of the degranulation of polymorphonuclear leukocytes. Rolipram has been proposed as an antidepressant; however, its use is accompanied by undesirable effects of the type involving nausea and vomiting.